Processes for fused cyclopropyl steroids



United States Patent 3,385,868 1 PROCEdSES FGR FUSE!) CYCLOPROPYLSTERGKDS Alexander D. Cross, Mexico City, Mexico, assignor te SyntaxCorperation, Eanama, Panama, a corperatien of Panama No Drawing.Continuation-impart of application fier. No. 441,318, Mar. 19, 1965.This application @ct. 15, 1965, Ser. No. 496,719 Ciaims priority,appiicatien Mexico, Apr. 17, 1964, 76,755 23 Claims. ((31. are-397.4

ABSTRACT 025 THE DESCLGSURE Process of introducing a fused cyclopropylgroup across a double bond of a steroid nucleus in an allylic orhomoallylic position with respect to a pre-existing hydroxyl group, thecyclopropyl group having a cis configuration with respect to thehydroxyl group. Process of cleaving such fused cyclopropyl group toyield a methyl group having the same configuration.

This invention is a continuation-in-part of Ser. No. 441,318, filed Mar.19, 1965, now abandoned.

The present invention is related to a novel procedure for thepreparation of cyclopentanophenanthrene derivatives.

More particularly, the present invention is related to a novel procedurefor introducing a methylene group into vicinal carbons of the steroidnucleus in a position allylic or homoallylic with respect to apre-existing hydroxyl group, from the corresponding compounds which havea double bond between such vicinal carbons.

In particular, this invention is related to the conversion of a steroidwith a free hydroxyl, in an allylic or homoallylic position with respectto a double bond, into the corresponding steroid having a cyclopropanering in lieu of the double bond and having a cis configuration withrespect to the hydroxyl.

This invention is also directed at the process of cleaving such fusedcyclopropane rings to yield a methyl group having the same configurationas the cyclopropyl group.

The process of the present invention by which the cyclopropane ringcontaining derivatives are prepared comprises treating a steroid of thetype mentioned hereinbefore with an iodide of an iodomethyl metal,wherein the metal has an oxidation potential of between +0.25 v. and+1.18 v. (see Chtarles D. Hodgmen, Handbook of Chemistry and Physics,42nd ed., 19604961, Chem. Rubher Publishing Co., page 1740) preferablyabout +0.76 v. such as zinc or chromium, in the absence of alkyliodides.

The steroids which may serve as convenient starting materials for theprocess of the present invention may belong to the estrane, androstane,pregnane, cholestane, coprostane, stigmastone, ergostane, cardenolideseries, etc., including compounds of abnormal configuration in eachseries, e.g. 95 compounds. The starting compound, in addition to thedouble bond-allylic or homoallylic hydroxyl grouping, may have presentin the molecule a variety of other substituents without having theseinterfere with the reaction, such as hydroxyls in positions differentfrom that mentioned, lower alkyl, especially methyl, and/ or halogens atany position on the molecule, free or ketalized ketonic groups, oracyloxy groups, on any carbon of the molecule.

The iodo-methyl iodide mentioned hereinbefore which constitutes thebasic reagent of one process of the present invention, may be preparedbefore the reaction and then the steroid may be treated with saidreagent, or it ICC may be prepared in situ, i.e., when the steroid isalready present. In any case, this reagent is obtained by treatment ofmethylene iodide with a metal having an oxidation potential comprisedwithin the limits mentioned hereinbefore, or preferably with a couple ofsaid metal with another metal having an oxidation potential betweenapproximately 0.3 and 1.7 v., such as copper, mercury, silver,palladium, etc., optionally in a solvent of the type used for thereaction, and preferably at reflux temperature from about 1 to 4 hoursand if desired, in the presence of catalytic amounts of iodine. Examplesof metal couples which are suitable and may be prepared by conventionalmethods known to the one skilled in the art, are: zinc-silver,chromium-copper, chromium-palladium, and the like.

The novel reaction object of the present invention is carried out in anorganic solvent, preferably in a hydrocarbon solvent having one or moreether functions in the molecule, such as ethyl-ether, dioxane,tetrahydrofuran, the dimethyl ether of diethyleneglycol(diglyme), thedimethyl ether of triethyleneglycol(triglyme), and the like.

Heretofore, when reaction of iodo-methyl-Zinc iodide is applied tounsaturated steroid compounds under the conditions specified in theliterature for other more simple compounds, very low yields areobserved, especially when the double bond is placed between tWo tertiarycarbon atoms, for example between C5 and C10, between C-8 and C-9, orbetween C13 and C-14. According to the present invention, the discoveryhas been made that upon elimination of the a kyl iodides (which arealways present in the reaction mixture as a consequence of secondaryreactions), for example, by heating such mixture to a temperature higherthan the boiling point of such alkyl iodides and allowing the resultingvapors to escape, quasiquantitative yields are obtained during theprincipal reaction. The alkyl iodides which are more frequently presentare methyl iodide and ethyl iodide, therefore it is generally sufficientto heat the mixture to a temperature higher than C. and preferablyhigher than C., at atmospheric pressure, for approximately 20 minutes to6 hours. In the cases where solvents are used which have a boiling pointlower than the limits indicated hereinbefore, such as for example, ethylether or tetrahydrofuran, it is preferred to evaporate a fraction of thereacting mixture, which may be comprised between approximately 5% and ofthe totality of said mixture, thus being eliminated the undesired alkyliodides. Once this alkyl iodide has been eliminated, the reaction iscontinued for from about 30 minutes to about 48 hours, or preferablyunder a pressure higher than the atmospheric pressure at temperatures offrom approximately 50 C. to 200 C.

The isolation of the resulting compounds may be carried out byconventional methods such as evaporation of the solvents followed bypurification, crystallization, chromatography, etc.

To sum up, the process of the present invention comprises putting incontact a steroid of the type described hereinbefore which has presentin the molecule a double bond-allylic or homoallylic hydroxyl system,with at least 1 molar equivalent and preferably an excess of aniodomethyl metal iodide, in a suitable solvent, during a period of timecomprised between about 5 minutes and 2 hours, preferably at refluxtemperature, subsequently eliminating the alkyl iodide, preferably byevaporation, either by heating the mixture or by simultaneousevaporation, of a fraction of the solvent, and subsequently continuingthe reaction for about 30 minutes to 48 hours, preferably under apressure higher than the atmospheric pressure at temperatures between 50C. and 200 C., to yield the corresponding steroids having a methylenegroup (a fused cyclopropyl group) attached to the carbons which werepreviously linked by a double bond and in position cis with respect tothe allylic or homoallylic hydroxyl. In case that two hydroxyls arepresent, one allylic and one homoallylic, the methylene group will beintroduced into the product in the cis position with respect to theallylic hydroxyl. The pressure under which the reaction is effected mayvary between approximately 1.1 and 20 atmospheres.

Examples of suitable starting compounds for the present invention are:pregnenolone; dioxgenin; A -androdihydroxy diosgenin; A androsteue35,176,19 triol; A androstene 30:,17/3 diol; A -androstene-3fi,178-di0l; A -dehydro 12 hydroxy tigogenin; cholesterol; A -estrene 311,175diol; A -9;8-estrene-3(1,175- diol; 16m chloro A -estrene-30:,17fl-di0l;17a-methyl- A -estrene 3a,6oc,l7 3 triol; 17a ethyl M -9,8- estrene30c,6oc,17fi triol; 6,8 methyl A androstene- 313,17fi diol; 6,6 dimethylA cholestene 3,7 diol; A cholesteue 35,175 diol; A-cholestene-3;8,7/3-diol; A 9,3 androstene 33,6;8 diol 17 one;anhydrostrophantidine; ergosterol; A pregnene 35,7,110; triol- ZO-one;19-nor-A -9B-pregnen-3u-ol-20-one, etc.

The process of the present invention makes possible the obtention, withgood yields, of steroids having a cyclopropane ring, of great interestfor their pharmaceutical uses, as for example, 5a,10eme'thylene-estnane-30:,17fl-di0l and 160s chloro 5a,10a-methylene-estrane- 30:,17 3-di0l,which exhibit anti-estrogenic, anti-gonadatrophic and anti-fibrillatoryproperties.

In addition, the compounds obtained by the process of the presentinvention are intermediate products for the production of compoundshaving pharmaceutical properties of importance, known to those skilledin the art. For example, 5a,l0oc methylene estrane 30:,17/3 diol, 17mmethyl 504,100: methylene estrane-3a,17/8-diol and 17m ethyl 5a,10amethylene estrane 30:,176- diol by catalytic hydrogenation, as withplatinum oxide, produce the corresponding Illa-methyl derivatives, whichupon conventional oxidation at C-3, followed by conventionaldehydrogenation between C-4 and C-5 produce the important correspondingA -3-keto-10u-methyl derivatives, which are in part the subject ofBelgian Patent No. 577,616. Likewise, a 3a-hydroxy-A -9/3 steroid may beinitially converted according to the process of this invention to a3a-hydroxy-5u,10a-methylene-9fl steroid and upon hydrogenation of saidsteroid according to the second aspect of this invention, there isobtained the corresponding 30; hydroxy a methyl 9B steroid, i.e.retrosteroids in which the configuration at the 9- and IO-carbon atomsis reversed from that of normal steroids. In the same manner, theobtention of Slice-methylenepregnan-Bfi-ol-ZO-one from pregnenolone bythe process of the present invention, may lead to the 6(0: or 3)- methylprogesterone by energetic hydrogenation followed by oxidation of thehydroxyl group and conventional dehydrogenation between C-4 and C5. The6-methylprogesterone has pharmaceutical properties of great importance,known to the one skilled in the art.

While the foregoing conversions have been typified by compounds whereinthe 3-hydroxy group controls the orientation of the methylene group uponaddition to the double bond, it is apparent that hydroxy groups in otherpositions may be utilized in this reaction. Thus, for ex- :ample, 19hydroxy A androstene may be employed for the introduction of a518,6;8-methylene group; and in a totally analogous manner to thatdescribed above, the Sama -methylene group may then be cleaved to yieldthe corresponding 6 3-methyl steroid. Similarly, a ll-hydroxy group maybe utilized to direct the introduction of a methylene group in a5,10-dehydro steroid, the configuration of this methylene group againbeing the same as that of the ll-hydroxy group. Upon utilization of thesecond aspect of this invention, this 5,10-methylene group (fusedcyclopropane ring) may then be cleaved to yield a 10- methyl group ofthe same configuration as the methylene group.

The specific examples set forth hereinafter, are intended to illustratethe present invention, not to limit its scope.

PREPARATION 1 A solution of 1 g. of A -estrene-3,17-dione (U.S. Patent2,729,654) in 50 cc. of tetrahydrofuran was added over a period of 30minutes to a stirred suspension of 1 g. of lithium aluminum hydride and50 cc. of anhydrous tetrahydrofuran. The mixture was heated to refluxduring 2 hours, then it was cooled and treated cautiously with 50 cc. ofethyl acetate and 2 cc. of water. Solid sodium sulfiate was added andthe inorganic material was filtered off and washed conscientiously withhot ethyl acetate, the combined organic solutions produced byevaporation a crude material, which was purified by crystallization fromacetone-hexane thus giving A -estrene-3u,17/3-dio1.

The known compounds specified under I were treated in the same manner togive the corresponding products listed under II:

PREPARATION 2 I II Atetatc of A (10) -estren-3B-ol'6,17- A-estrcne-3B,6a, 17B-triol.

10116. 3-acetate of Her-methyl-A 17a-rnethyl-A -estreuc-3fl,6a,

estrenc-3B,17fl-diol6-one. 17B-triol.

Example 1 A mixture of 4 g. of methylene iodide, 1 g. of zinc coppercouple (prepared according to H. 'E. Simmons and R. D. Smith, J. Am.Chem. Soc. 81, 4256 (1959)) and 20 cc. of ethyl ether were boiled underreflux during 1 hour. The resulting mixture was filtered and thefiltrate was added to a solution of 1 g. of A -estrene- 3a,l7/3-diol in20 cc. of ethyl ether. The whole was boiled under reflux during 1 hour,then 15 cc. of solvent were evaporated and the liquid residue wasintroduced into a sealed tube, which was maintained at 100 C. during 2hours. The tube was cooled, the content was diluted with ether, washedsuccessively with 10% ammonium chloride solution, a 5% sodium carbonatesolution, then with water to neutral, dried over sodium sulfate andevaporated to dryness. The solid residue was chromatographed on a columnof 20 g. of alumina thus giving 5d,].06t-methylene-estrane-3a,17fi-diol.Yield:

Example 2 A mixture of 3.6 g. of zinc copper couple, 11.5 g. ofmethylene iodide, 50 cc. of anhydrous ethyl ether, 0.02 g. of iodide and5 g. of 17u-methyl-A -estrene-Ba,6a 17fi-triol was refluxed withstirring during 1 hour. Then 15 cc. of solvent were evaporated and theliquid residue was introduced into a sealed tube. The tube was heated to80 C. during 6 hours. Then the contents were diluted with cc. of ethylether, thus giving a mixture which was washed consecutively with asolution of 5% hydrochloric acid, and aqueous 5% sodium bicarbonatesolution, and water to neutral, the organic layer was dried over sodiumsulfate, evaporated to dryness and the resulting residue waschromatographed on alumina to give 170: methyl 5a,l0u methylene estrane30,6oc,17fitriol. Yield: 85%.

Example 3 The procedure of Example 1 was repeated, except that insteadof zinc copper couple there was used Zinc-silver, which was prepared inthe same manner, substituting only the copper compound by silvercompound, thus being obtained the same final product.

Example 4 The process of Example 2 was repeated with the exception thatzinc copper couple was substituted by chromiumcopper couple which inturn was prepared in identical manner, only substituting zinc-dust bychromium dust, thus being obtained the same final compound.

Example 5 The procedure described in Example 1 was repeated except thatethyl ether was substituted by tetrahydrofuran and the reaction in asealed tube was carried out during 3 hours at 150 C., thus beingobtained the same final compound.

Example 6 5 g. of 17a-methyl-A -estrene-3a,6a,l7/3-triol were treated bythe procedure described in Example 2, except that ethyl ether wassubstituted by dioxane and the reaction in the sealed tube was effectedat 170 C., during 3 hours, thus being obtainedl7ot-methyl-5a,lOa-methyI- ene-estrane-3u,6a,l7fi-triol.

Example 7 A mixture of 2 g. of zinc-copper couple, 7 g. of methyleneiodide, 150 cc. of the dimethyl ether of diethyleneglycol (diglyme) and2 g. of l7a-ethyl-A -estrene- 3a,6oc,l7/3-tfi0l was heated to 100 C., inan opened flask during 2 hours, then it was refluxed during 48 hours,cooled and washed successively with an aqueous 10% ammonium chloridesolution, a 5% aqueous sodium bicarbonate solution and water to neutral.The organic solution was dried over sodium sulfate and evaporated todryness under reduced pressure. The residue was chromatographed onalumina thus giving l7a-el2hyl-5a,l0amethyIene-estrane-Sufiu,17,8-triol.Yield: 70%.

Example 8 The compounds listed under I were treated according to Example1 to give the corresponding products specified under 11:

5a,10a-methylene-19-nor-22-isospirostane 3;8,6a-diol.

5a,IOtz-methylene-IQ-norpregnane- 3 3,6r1,20fl-triol.

17,20;20,ZI-hismethylenedioxy-5a,IOa-rnethylene-lQ-uorpregnane-3t3,6a-diol.

55,63-methylene-pregnan-3fl-ol- ZOcne.

56, (MS-methylene androstan-3B,

7s- 1B,Zdmethylene-GB-methylan- 101. 17,20;20,21-bismethylenedioxy- A-l9-nor-pregnene-3fi,fia-diol.

Pregnenclone A -androstene3fi,17fi-diol fifi-r nethyl-A androstsue-36,173- Two grams of 5a,l0a-methylene-9B-estrane-3a,l7/8-diol, ml. of aceticanhydride and 20 ml. of pyridine are heated at steam-bath temperaturefor one hour. At the end of this time the reaction mixture is evaporatedto dryness and the solid thus obtained is recrystallized from hexane toyield 3a,l7 3-diacetoxy-Su,10u-methylene-9B- estrane.

One gram of this material in 20 ml. of acetic acid is hydrogenated inthe presence of pre-reduced platinum oxide and a pressure of 40atmospheres. Upon the absorption of the theoretical amount of hydrogen,the reaction mixture is filtered and the filtrate is evaporated todryness to yield 3a,17,8-diacetoxy-9a,l0u-androstane. This material maybe hydrolyzed by refluxing it with 2 g. sodium hydroxide and 50 ml. ofmethanol for one hour, followed by precipitation through the addition ofwater and collection of the solid by filtration. There is thus obtained9B,lOa-androstane-B'a,l7B-diol which may be modified according toconventional routes employed for the corresponding androstanes of normalconfiguration.

Other steroids having a reversed configuration at positions 9 and 10,i.e. a retrosteroid, may be provided according to this procedure. Thus,for example, l9-nor- A -9B-pregnen-3a-ol-2O-one may be converted to9,8,10u-pregnan-Sa-oI-ZO-One via this process.

Likewise other compounds of the present invention having a cyclopropanegroup in other positions may be converted to the corresponding methylcompound according to the procedure of this example.

I claim:

1. A process which comprises treating a steroid containing a groupselected from a double bond with a homoallylic hydroxyl group and adouble bond with an allylic hydroxyl group with an iodo-methyl metaliodide, wherein the metal has an oxidation potential between +0.25 v.and +1.18 v. in a hydrocarbon solvent having in the molecule at leastone ether function, in the absence of alkyl iodide, to give thecorresponding steroid having a cyclopropane grouping in position ciswith respect to the hydroxyl group.

2. The process of claim 1 wherein the metal is zinc.

3. The process of claim 1 wherein the solvent is ethyl ether.

4. The process of claim 1 wherein the solvent is tetrahydrofuran.

5. The process of claim 1 wherein the solvent is dioxane.

6. The process of claim 1 wherein the alkyl iodides are eliminated byevaporation of a fraction of the solvent.

7. The process of claim 1 wherein the starting steroid has a double bondbetween 0-5 and C-1().

8. A process for obtaining a steroid comprising in the molecule acyclopropane grouping with configuration cis with respect to a hydroxylgroup selected from the group consisting of an allylic and a homoallylichydroxyl group which comprises reacting the corresponding steroidscontaining a group selected from a double bond-allylic hydroxyl and adouble bond-homoallylic hydroxyl group, with iodo methyl Zinc iodide inethyl ether, eliminating the formed alkyl iodides by evaporation of afraction of the reaction mixture, and continuing the reaction under apressure higher than the atmospheric pressure, at temperatures between50 C. and 200 C. over a period of from about thirty minutes to about 48hours.

9. The process of claim 8, wherein the starting compound is A-estrene-3fi,6a,l7,B-triol.

10. The process of claim 8, wherein the starting compound is A-19-nor-pregnene-3fl,6a,20B-triol.

11. The process of claim 8, wherein the starting compound is17a-methyl-A -estrene-3a,6u,17 3-triol.

12. The process of claim 8, wherein the starting compound is A -estrene30:,17B-di0l.

13. The process of claim 8, wherein the starting compound ispregnenolone.

14. The process of claim 8 wherein the starting com pound is A-androstene-3 5,17,8-diol.

15. The process of claim 8 wherein the starting steroid has a doublebond between C-5 and C-6.

16. The process of claim 8, wherein the starting compound has a 9Bconfiguration.

17. The process of claim 8, wherein the starting compound is A-9;6-estrene having a 3a-hydroxy group.

18. The process of claim 8, wherein the hydroxyl group is in the C-19position.

19. The process of claim 8 including the step of hydrogenating the fusedcyclopropyl steroid whereby the cyclopropyl group is converted to amethyl group having the same configuration as the cyclopropyl group.

20. The process of claim 19, wherein a 5a,10a-methylene steroid isconverted to a wet-methyl steroid.

21. The process of claim 19, wherein a 5,8,10B-methylene steroid isconverted to a IOB-methyl steroid.

References Cited UNITED STATES PATENTS Ginsig et al., Journal Org. Chem.(1966), pp. 1761-1764 relied on.

ELBERT L. ROBERTS, Primary Examiner.

